Search PubMed⌕ Search

Biomedical subjects

G Mason

Publications and source records attributed to G Mason.

At least 91 records · Page 5Linked to original sources
PubMed1986

Monoclonal antibodies to chlorinated dibenzo-p-dioxins.

A thyroglobulin conjugate of dioxin (thyroglobulin-2 adipamide, 3,7,8-trichlorodibenzo-p-dioxin) (TG-TCDD) was used to immunize BALB/c mice. Hybridomas were produced by cell fusion between immune spleen cells and mouse myelomas SP2/0, P3, or NS1. To screen the thousands of resultant cultures for production of monoclonal antibodies (MoAb), a rapid, solid-phase radioimmunoassay for antibody to dioxins was developed. This procedure involved attaching bovine serum albumin coupled with trichlorodibenzo-p-dioxin (BSA-TCDD) to polystyrene plates to be used as a solid-phase target antigen for reaction with MoAb. Fourteen hybridomas were identified that produced MoAb reacting with BSa-TCDD but not with BSA alone. Antibodies were tested for binding to BSA-aniline to eliminate those with limited binding specificity. Initial studies indicated that most MoAbs bound BSA-aniline as well as BSA-TCDD. More detailed analyses indicated that while most MoAbs showed some reaction with BSA-aniline, two showed preferential binding to BSA-TCDD of more than 200-fold whereas rabbit antisera demonstrated only a 5-fold discrimination. MoAb 391-1B was purified from mouse ascites fluid and after radioiodination, was tested for direct binding to BSA-TCDD or BSA-aniline. 125I-MoAb 391-1B showed no significant binding to BSA-aniline while demonstrating high binding to BSA-TCDD (Ka = 4.5 X 10(8) liters/mol).

Amides↗
PubMed1986

Polychlorinated dibenzo-p-dioxins: quantitative in vitro and in vivo structure-activity relationships.

There were marked effects of structure on the activities of 14 polychlorinated dibenzo-p-dioxins (PCDDs) as competitive ligands for the 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) receptor and as inducers of aryl hydrocarbon hydroxylase (AHH) and ethoxyresorufin O-deethylase (EROD) in rat hepatoma H-4-II E cells in culture. 2,3,7,8-TCDD was the most active compound in both assays and several PCDD congeners which were fully substituted in the lateral 2, 3, 7 and 8 positions but also contained additional chlorosubstituents in non-lateral 1, 4, 6 and 9 positions were less active. It was also evident that there was a decrease in in vitro binding and induction activities with decreasing lateral chlorine substitution. Although comparable structure-activity relationships (SARs) for the PCDDs were observed for the induction and receptor binding assays, there was not a linear or rank order correlation between the 2 sets of data. Several in vivo biologic and toxic activities of 2,3,7-trichloro-, 2,3,7,8- and 1,3,7,8-tetrachloro-, 1,2,4,7,8- and 1,2,3,7,8-pentachloro- and 1,2,3,4,7,8-hexachlorodibenzo-p-dioxin were determined in a dose-response fashion in immature male Wistar rats. The ED50 values for hepatic microsomal AHH and EROD induction, body weight loss and thymic atrophy were obtained. There was an excellent linear correlation between the -log EC50 values for AHH or EROD induction in cell culture and the -log ED50 values for enzyme induction, body weight loss and thymic atrophy in the rat. The in vitro enzyme induction data could be used to quantitatively estimate the toxicity of the PCDD congeners in the rat: this latter correlation has previously been observed for a series of polychlorinated dibenzofurans.

Animals↗
PubMed1986

The biologic and toxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin in chickens.

The administration of 2,3,7,8-TCDD to 2-week-old White Leghorn cockerels produced a dose-dependent induction of hepatic microsomal ethoxyresorufin O-deethylase (EROD) and benzo[alpha]pyrene (B[alpha]P) hydroxylase activities with induction EC50 values of 778 and 302 ng/kg, respectively. In addition, 2,3,7,8-TCDD also induced 4-dimethylaminoantipyrine (DMAP) N-demethylase (EC50 = 561 ng/kg), this result contrasting with studies reported for other animal species in which 2,3,7,8-TCDD either does not induce or inhibits this cytochrome P-450 dependent monooxygenase enzyme activity. However, the reduced cytochrome P-450:CO binding difference spectral absorption maxima for the 2,3,7,8-TCDD induced microsomes was observed at 448 nm which was similar to that reported for most animals which have been investigated. Electrophoresis of control and 2,3,7,8-TCDD induced microsomal proteins using SDS polyacrylamide slab gels showed intensification of 3 protein staining bands at Mr 53 000, 56 000 and 58 000. Incubation of the 2,3,7,8-TCDD-induced microsomes with SKF-525A and alpha-naphthoflavone showed that both compounds inhibited DMAP N-demethylase, EROD and AHH and that alpha-naphthoflavone was the more potent inhibitor of all 3 microsomal monooxygenases. 2,3,7,8-TCDD treatment caused significant involution of the Bursa of Fabricius when administered at a dose level of 10 micrograms/kg for 3 days and this result confirmed the extreme sensitivity of the immature White Leghorn cockerel to the biologic and toxic effects elicited by 2,3,7,8-TCDD. However, in contrast to other sensitive species, no high affinity cytosolic receptor protein for [3H]2,3,7,8-TCDD could be detected in the liver of chick embryos or 2-week-old birds.

Animals↗
PubMed1986

Synthesis, biologic and toxic effects of the major 2,3,7,8-tetrachlorodibenzo-p-dioxin metabolites in the rat.

The two major mammalian metabolites of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), namely 2-hydroxy-3,7,8-trichlorodibenzo-p-dioxin and 2-hydroxy-1,3,7,8-tetrachlorodibenzo-p-dioxin, have been synthesized. The compounds were individually administered to immature male Wistar rats and their effects on body weight loss, thymic atrophy, liver and spleen weights and their activities as inducers of hepatic microsomal benzo[a]pyrene hydroxylase, 4-chlorobiphenyl hydroxylase and ethoxyresorufin O-deethylase were determined using dose levels of 100, 1000 and 5000 micrograms/kg. The 2 metabolites did not affect organ or body weights after 14 days of exposure and only 2-hydroxy-3,7,8-trichlorodibenzo-p-dioxin was active as an inducer of the microsomal monooxygenases at dose levels of 1000 and 5000 micrograms/kg. A comparison of the relative enzyme induction activities of 2,3,7,8-TCDD and 2-hydroxy-3,7,8-trichlorodibenzo-p-dioxin indicates that the former compound was greater than 3 orders of magnitude more active than the metabolite.

Animals↗
PubMed1985

Polychlorinated dibenzofurans (PCDFs): correlation between in vivo and in vitro structure-activity relationships.

Fifteen polychlorinated dibenzofuran (PCDF) congeners were administered in a dose-response fashion to immature male Wistar rats and ED50 values for body weight loss, thymic atrophy and the induction of the hepatic microsomal cytochrome P-448-dependent monooxygenases, aryl hydrocarbon hydroxylase (AHH) and 4-chlorobiphenyl hydroxylase were determined. There was an excellent correlation between the in vivo quantitative structure-activity relationships for these PCDFs and their in vitro activities as AHH inducers in rat hepatoma H-4-II E cells and as ligands for the 2,3,7,8-TCDD receptor protein. A comparison of isomers which differ at all 4 positions in the dibenzofuran ring system indicated that chlorine substitution at each position contributed differentially to the overall molecular activity [C-3 (or C-7) greater than C-2 (or C-8) greater than C-4 (or C-6) greater than C-1 (or C-9)]. There was also an excellent linear correlation between a plot of the -log ED50 for body weight loss vs. -log EC50 for in vitro AHH induction (correlation coefficient, r = 0.96) and -log ED50 for thymic atrophy vs. -log EC50 for in vitro AHH induction (correlation coefficient, r = 0.88). Since body weight loss and thymic atrophy in the rat are representative toxic responses to PCDFs and related toxic halogenated aryl hydrocarbons, the correlations noted above support the use of the in vitro AHH induction assay as a short term quantitative test system for this class of toxic halogenated aryl hydrocarbons.

Animals↗
PubMed1985

Modulation of rat hepatic microsomal testosterone hydroxylases by 2,3,7,8-tetrachlorodibenzo-p-dioxin and related toxic isostereomers.

The effects of several toxic halogenated aryl hydrocarbons including 2,3,7,8-tetrachlorodibenzo-p-dioxin, 2,3,7,8-tetrachlorodibenzofuran, 2,3,4,7,8-pentachlorodibenzofuran, 3,3',4,4'-tetrabromobiphenyl, 3,3',4,4'5-pentachlorobiphenyl, and 3,3',4,4'-tetrachloroazobenzene on hepatic microsomal testosterone hydroxylases were determined in the immature male rat. All of these compounds induced hepatic testosterone 7 alpha-hydroxylase and inhibited testosterone 6 beta-, 16 alpha-, 16 beta-, and 2 alpha-hydroxylases and androstenedione formation. It was observed that there was a good correlation between the increase in testosterone 7 alpha-hydroxylase by the halogenated hydrocarbons and their ability to cause body weight loss in the exposed rats. Comparable linear correlations were observed between toxicity and the decreased activities of other testosterone hydroxylases. The role of altered testosterone metabolism in the toxicity of halogenated aryl hydrocarbons is unknown.

Animals↗
PubMed1985

Effects of structure on binding to the 2,3,7,8-TCDD receptor protein and AHH induction--halogenated biphenyls.

The quantitative structure-activity relationships (QSARs) for polychlorinated biphenyl (PCB) congeners have been determined by comparing the EC50 values for three in vitro test systems, namely, aryl hydrocarbon hydroxylase (AHH) and ethoxyresorufin O-deethylase (EROD) induction in rat hepatoma H-4-II-E cells and competitive binding avidities to the rat cytosolic receptor protein (using 2,3,7,8-tetrachlorodibenzo-p-dioxin as a radioligand). For several PCB congeners that are in vivo inducers of rat hepatic microsomal AHH, there was a linear correlation between the -log EC50 values for receptor and the -log EC50 values for AHH (or EROD) induction; moreover, a comparable linear relationship was observed between the -log EC50 values for AHH and EROD induction. Previous in vivo studies have shown that the most active PCB congeners 3,3',4,4'-tetra-, 3,4,4',5-tetra-, 3,3',4,4',5-penta-, and 3,3',4,4',5,5'-hexachlorobiphenyl, cause many of the biologic and toxic effects reported for the highly toxic halogenated aryl hydrocarbon, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Moreover, the monoortho-substituted homologs of the four coplanar PCBs also elicit comparable in vivo biologic and toxic responses. It was evident from the QSARs for PCBs that there was an excellent correspondence between the in vivo and in vitro potencies of the individual PCB congeners. The effects of substituents on both receptor binding and AHH/EROD induction was determined for a series of 4'-substituted (X)-2,3,4,5-tetrachlorobiphenyls (where X = H, Cl, Br, I, OH, OCH3, NO2, COCH3, F, CF3, CH3, C2H5, i-C3H7, n-C4H9 and t-C4H9). Not unexpectedly, there was a linear relationship between the -log EC50 values for AHH and EROD induction, and these results confirm that both enzymatic oxidations are catalyzed by the same cytochrome P-450 isozyme(s). The effects of substituent structure on receptor binding for 12 substituents was subjected to multiple regression analysis which correlates the relative binding affinities of the compounds with the physical chemical characteristics of the substituents. The analysis gave the following equation: log (1/EC50) = 1.53 sigma + 1.47 pi + 1.09 HB + 4.08 for n = 12, s = 0.18, r = 0.978; where n is the number of substituents, s is the standard deviation, r is the correlation coefficient, and sigma = electronegativity, pi = hydrophobicity (log P) and HB = hydrogen bonding capacity for the substituent groups.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1984

Effect of manganese treatment on the levels of neurotransmitters, hormones, and neuropeptides: modulation by stress.

Six weeks of daily intraperitoneal injection with manganese chloride (15 mg/kg body wt) reduced the normal weight gain of male Fischer-344 rats. This treatment depressed plasma testosterone and corticosterone levels, but prolactin levels were unaffected. The only significant changes in the levels of a variety of neuropeptides assayed in several regions were increases in the levels of hypothalamic substance P and pituitary neurotensin. Striatal serotonin, dopamine, and their metabolites were unchanged in manganese-exposed rats relative to saline-injected controls. However, the stress of injection combined with the effect of manganese appeared to significantly increase concentrations of striatal monoamines relative to uninjected controls.

Animals↗
PubMed1984

Persistent vaginal estrus and serum hormones after chlordecone (kepone) treatment of adult female rats.

The effects of chlordecone on vaginal estrus and neuroendocrine responses were examined in adult ovariectomized and intact females. Persistent vaginal estrus was seen in females given 50 mg/kg or more of chlordecone. The development of vaginal estrus was similar to that seen in ovariectomized females after treatment with estrogen. Since chlordecone is known to have estrogen-like effects on the reproductive system, the persistent vaginal estrus probably results from this estrogen-like action and chlordecone's long half-life in the organism. Neuroendocrine effects of chlordecone also resembled, to some degree, estrogen's effects on pituitary secretions. Chlordecone increased serum prolactin and decreased serum luteinizing hormone (LH) in ovariectomized females 30 to 36 hr after a single exposure to 50 mg/kg of the pesticide. Basal LH levels were not altered in intact females, but the proestrous LH surge was suppressed by 36 hr after treatment. Both basal and proestrous levels of prolactin were suppressed. Unlike the effects of estrogen, serum follicle stimulating hormone was not altered by chlordecone. These results indicate an effect on the hypothalamic pituitary axis by chlordecone treatment and offer a possible explanation for the reduced fertility seen in adult females after chlordecone exposure. However, blockage of the proestrous LH surge was not obligatory for the appearance of vaginal estrus. Although chlordecone produced peripheral changes in the vaginal smear pattern as well as neuroendocrine alterations, the peripheral changes were not always indicative of the neuroendocrine events.

Animals↗
PubMed1984

Polychlorinated dibenzofurans (PCDFs): effects of structure on binding to the 2,3,7,8-TCDD cytosolic receptor protein, AHH induction and toxicity.

The effects of structure on the activity of 26 polychlorinated dibenzofurans (PCDFs) as competitive ligands for the 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) rat hepatic cytosolic receptor protein were determined in a dose-response fashion. The ED50 values for these compounds varied 100 000-fold and the most active PCDFs were substituted in the 2,3,7 and 8 lateral positions; the ED50 for the most active PCDF, 2,3,4,7,8-pentachlorodibenzofuran was 1.5 X 10(-8) M which was only slightly less active than 2,3,7,8-TCDD (1.0 X 10(-8) M). A comparison of the binding affinities of several isomer pairs also indicated the relative importance of chlorine substitution at C-4 (or C-6) compared to C-1 (or C-9). Moreover, for some isomers it is apparent that C-4 (or C-6) substituents are more active than lateral substituents for facilitating ligand binding to the receptor protein. This is illustrated by the relative binding potencies of the following isomer pairs: 1,2,4,6,7-/1,2,4,7,8 = 19.2; 2,6,7-/2,3,8- = 2.2; 1,3,6-/1,3,8- = 19. Most of the PCDF structure-activity effects noted above were also observed for the induction of aryl hydrocarbon hydroxylase (AHH) and ethoxyresorufin O-deethylase (EROD) in rat hepatoma H-4-II-E cells in culture. The most active compounds were also substituted in the lateral 2,3,7 and 8 positions and a comparison of C-4 (or C-6) vs. C-1 (or C-9) substituted PCDFs confirmed the higher induction potencies for most of the former group of compounds. The in vitro quantitative structure-activity data were complemented by in vivo studies which determined the relative activities of selected PCDFs as inducers of hepatic microsomal cytochrome P-448 dependent monooxygenases and their effects on body weight gain and thymus weights in immature male Wistar rats. The results indicated that for 2 series of isomers, namely the 2,3,4,7,8-, 1,2,4,7,8- and 1,2,4,7,9-pentachlorodibenzofurans and the 2,3,7,8-, 2,3,4,8- and 1,2,4,8-tetrachlorodibenzofurans, their biologic and toxic potencies were dependent on one major structural factor, the number of lateral chloro substituents. These results support the proposed role of the cytosolic receptor protein in mediating the biologic and toxic effects of the PCDFs.

Animals↗
PubMed1983

Blood monocyte aryl hydrocarbon hydroxylase activity in psoriasis.

The activity of aryl hydrocarbon hydroxylase (AHH) in monocytes from 13 healthy control subjects and in 16 patients with discoid psoriasis was measured. The mean basal monocyte AHH activities of the control and psoriatic groups were 3.4 +/- 0.47 and 4.46 +/- 0.55 respectively (pmol 3-OHBP h-1 10(-6) cells). This difference was not significant. The mean induced monocyte AHH activities in the control and psoriatic groups were 56.4 +/- 10.8 and 77.8 +/- 16.0 pmol 3-OHBP h-1 10(-6) cells respectively but this difference was not significant. The mean induction ratios in the control and psoriatic groups were 16.5 +/- 1.8 and 20.4 +/- 3.6 respectively. Again, this difference was not significant. We conclude therefore, that monocyte aryl hydrocarbon hydroxylase activity is not reduced in psoriasis.

Adult↗
PubMed1982

Interactions between "handling" and acrylamide on endocrine responses in rats.

Serum prolactin and corticosterone levels were measured in rats that had been gentled by handling and that had been exposed to 100 mg/kg acrylamide. Handling reduced both corticosterone and prolactin levels. Acrylamide had no effect on corticosterone levels. Prolactin levels were significantly lower in acrylamide-exposed nonhandled animals. These findings are discussed in terms of their implications for studying the effects of toxicants on neural function.

Acrylamides↗
PubMed1981

Asymmetric distribution of carbonic anhydrase in the alveolar-capillary barrier.

Pulmonary carbonic anhydrase (CA) activity was studied by injecting 0.5 ml of a buffered solution of NaH14CO3 and 3H2O into the distal airways of perfused rabbit lungs. The early recovery of 14C in the pulmonary venous outflow averaged 0.28 +/- 0.02 (SE) that of 3H under control circumstances. Incorporation of a CA inhibitor (20 mg/l acetazolamide) in the perfusate reduced 14C recovery relative to 3H by two-thirds, whereas this inhibitor had no effect when placed in the airway injection fluid. Addition of 100 mg/l Ca to the perfusate did not increase 14C recovery, but addition of the enzyme to the bronchial fluid increased 14C recovery relative to 3H by a factor of more than 5. It is concluded that CA is associated with the endothelial side of the alveolar-capillary barrier but is absent on the airway surfaces.

Animals↗